Discovery of a Novel Cellular Inhibitor that Protects Against Cylin Dependent Kinase5 Induced Neurotoxicity

Download or read book Discovery of a Novel Cellular Inhibitor that Protects Against Cylin Dependent Kinase5 Induced Neurotoxicity written by Lingyan Zhang and published by . This book was released on 2010 with total page 182 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cylcine-dependent kinase 5 (Cdk5) is a member of the CDK family, but, distinct from other CDKs, it does not participate in cell cycle regulation. Instead, its activation requires association with its neuron-specific regulator p35 or p39 and, thus, Cdk5's activity has mainly been associated with the central nervous system (CNS). Cdk5-p35 complex has been found to be critical for post mitotic neuronal activities such as neurite outgrowth, axon guidance, neuronal migration and neuronal survival. Under pathological conditions, however, the p35 regulatory subunit can undergo proteolysis to form CDK5/p25 and a 10 kDa amino-terminal fragment, p10. While CDK5/p35 is essential for normal brain development and function, CDK5/p25 causes neuron death associated with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other human neurodegenerative disorders. While all studies have placed p25 at the center of attention, we have discovered that p10 may serve an important role in protecting neurons from toxicity associated with CDK5/p25. Our studies confirm the common wisdom that CDK5/p25 is inherently neurotoxic, but we herein propose that cell death per se is directly attributable to the rapid degradation of p10. Our research demonstrated the protective effect of p10 against toxicity induced by Cdk5-p25 complex in different cell types. We also showed that p10 can protect neurons from MPP+ induced toxicity and block neurons from cell cycle re-entry induced by aberrant CDK5/p25 activity. Interestingly, although p10 can reduce CDK5/p25 activity in cells, it doesn't directly inhibit CDK5/p25 kinase activity in vitro. This leads us to propose that p10 might associate with other proteins in cells to form protein complex, which is required for its protective effects against CDK5/p25.